Drug discovery is a costly and inefficient process. Many promising hits identified from initial screening are often excluded from further investigation due to their poor water solubility and/or low bioavailability. Incorporating drug formulation expertise early in the drug discovery process represents an important strategy to facilitate preclinical and clinical evaluations of promising candidates that are poorly water soluble. JP4-039 and XJB5- 131 are stable nitroxide (4-amino-TEMPO) antioxidants conjugated to a peptide fragment derived from gramicidin S to facilitate their enrichment in mitochondria. Therapeutic effects of these novel compounds have been extensively demonstrated in rat hemorrhagic shock model and various radiation models in mice. One of the major hurdles for these compounds to advance into clinical applications is their poor water solubility. Organic solvents such as ethanol, DMSO, Cremophor EL/ethanol had to be used in the past for the assessment of their in vivo activity. We initially developed an emulsion-based formulation that could be used for either systemic (i.p. and i.v.) or topical (skin) application. However JP4-039-loaded emulsion formulation is relatively unstable. The drug is slowly disassociated from the particles over time. Low drug loading capacity and formulation instability are common problems in formulating agents that are moderately hydrophobic, mostly due to inadequate mixing of the insufficiently hydrophobic agents with the highly lipophilic aliphatic chains in surfactants and oil core of emulsions. Drugs that are initially mixed with oil core tend to slowly move to the interface of emulsion particles and eventually are disassociated from the particles. We hypothesize that drugs that are poorly water soluble and moderately hydrophobic can be effectively incorporated into emulsion or micellar formulations via the use of a novel surfactant that has a built-in drug-interactive domain between the hydrophilic PEG and the lipophilic anchor. JP4-039 will be used as a model drug to test the hypothesis. Three aims will be pursued in this project. In Aim 1, we will synthesize and characterize a number of PEG-lipopeptides with various interactive domains to identify the optimal structure for micellar formulation of JP4-039. In Aim 2, we will examine the in vivo pharmacokinetics and biodistribution of JP4-039- loaded micelles. In Aim 3, we will investigate the therapeutic efficacy of JP4-039-loaded micelles in mouse models of irradiation and hemorrhagic shock. Successful completion of this study will lead to the development of a new strategy that will facilitate the in vivo application of not only JP4-039 but also many other therapeutics that are poorly water soluble and difficult to formulate with existing lipidic systems